Abstract
Purpose
AZD5438 is a novel, orally bioavailable, cyclin-dependent kinase (CDK) inhibitor demonstrating preclinical pharmacodynamic (PD) effects on CDK substrates and active growth inhibition of human tumour xenografts. Clinical pharmacokinetic (PK) data shows its plasma t 1/2 to be 1–3 h. The main purpose of the current study was to evaluate PD activity of single oral doses of AZD5438 in healthy volunteers. Twelve healthy male subjects received 10, 40 or 60 mg AZD5438 or placebo in a rotating placebo crossover study design. Rapidly proliferating normal tissues [buccal mucosa, peripheral blood mononucleocytes (PBMCs) and plucked scalp hair] were sampled pre-dosing, 1.5 h (t max), ±6 h post-dosing. The primary PD endpoint, phospho-retinoblastoma protein (pRb) levels in buccal biopsies (unit length labelling index) assessed by immunohistochemistry, was used as a biomarker of CDK activity.
Results
Phospho-pRb levels were demonstrated to decrease in an epitope, dose- and time-dependent manner. Statistically significant reductions in the ratio phospho-pRb/total pRb were detected at 1.5 h post-dose compared to placebo for both 40 mg [S807–S811 epitope geometric least-squares mean (glsmean) ratio = 0.75, P = 0.014] and 60 mg AZD5438 (S807–S811 epitope glsmean ratio = 0.74, P = 0.011; T821 epitope glsmean ratio = 0.72, P = 0.031). No statistically significant differences were noted at 6 h post-dosing, indicating a close PK–PD relationship between AZD5438 and target inhibition. No effects attributable to AZD5438 were detectable on phospho-p27, p27, Ki67 in the buccal mucosa; or on phospho-pRb (S249–T252 epitope), phospho-p27 or Ki67 in the sheath cells of plucked scalp hair, raising issues about the appropriateness of different detection methods/tissues for use as PD biomarkers. In ex vivo stimulated PBMCs, statistically and near-statistically significant anti-proliferative effects, with the suggestion of a dose–response effect, were noted on the incorporation of [3H]-thymidine (stimulated/non-stimulated) at 10, 40 and 60 mg, compared to placebo, at 1.5 h post-dosing (glsmean ratio = 0.65, P = 0.019; 0.70, P = 0.056; 0.51, P = 0.001, respectively).
Conclusions
The modest PD effect, short plasma t 1/2 and close PK–PD relationship suggest that multiple daily dosing or sustained release formulations at higher doses will be necessary for AZD5438 to achieve sustained inhibition of CDK in human cancers.
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Abbreviations
- CPU:
-
Clinical pharmacology unit
- UK:
-
United Kingdom
- mg:
-
Milligram
- kg:
-
Kilogram
- ml:
-
Millilitre
- DLT:
-
Dose-limiting toxicity
- SMC:
-
Safety monitoring committee
- MWTD:
-
Maximum well-tolerated dose
- PBMC:
-
Peripheral blood mononucleocyte
- Cpm:
-
Counts per minute
- ANCOVA:
-
Analysis of covariance
- glsmean:
-
Geometric least-squares mean
- CI:
-
95% Confidence intervals
- CV:
-
Coefficient of variance
- ULN:
-
Upper limit of normal
- t 1/2 :
-
Half-life
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Acknowledgments
With thanks to Sally Ward, John Freeman and Anita Lindsay (Study Team Management, AstraZeneca, Alderley Park), Graham Bigley, Debbie Oaks and Helen Wombewell (Discovery Medicine Histopathology Group, AstraZeneca, Alderley Park). There are no conflicts of interest for any of the authors.
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Camidge, D.R., Pemberton, M., Growcott, J. et al. A phase I pharmacodynamic study of the effects of the cyclin-dependent kinase-inhibitor AZD5438 on cell cycle markers within the buccal mucosa, plucked scalp hairs and peripheral blood mononucleocytes of healthy male volunteers. Cancer Chemother Pharmacol 60, 479–488 (2007). https://doi.org/10.1007/s00280-006-0387-2
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DOI: https://doi.org/10.1007/s00280-006-0387-2